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21-23 (36). Compounds 21-23 showed EC50 values of 0.19, 0.21 and 0.005 nM against P. falciparum in vitro, and 23 showed a 3000-fold selectivity for the parasite over FM3A mouse mammary cells. Compounds 21 and 22 were also effective in vivo against P. berghei in a murine model, showing ED5o values of 13 and 70 mg/kg by intraperitoneal administration.

Miscellaneous Antimalarial Agents - A number of synthetic agents and natural product derivatives have been shown to possess antimalarial activity. The herbal natural product (+)-febrifugine, 24 (Chinese name: chang shan) and its derivatives

possess significant antimalarial activity (37). Recently described semisynthetic febrifugine analogues such as 25 have remarkable antimalarial activity, with ECso values as low as 8.6 X 10"9 M against P. falciparum in vitro (38). Promising cure rates in humans have been attained by using atovaquone, 26 and proguanil, 27 in combination (39). The recently discovered phenanthrene halofantrine, 28, has also shown significant antimalarial activity in vitro (27), and bisquinoline heteroalkanediamines such as 29 (IC5o = 1 -2 nM) are effective against P. falciparum in vitro and in vivo (40). Potential new pharmacophores for antimalarial lead optimization are typified by calothrixins such as 30, which exhibit nanomolar IC5o values (41) and phenyl ß-methoxyacrylates such as 31, which has an in vitro IC5o of 0.06 ng/mL, and an in vivo effect at 100 mg/kg (42). Dibenzosuberanylpiperazine derivatives such as 32 possess weak to modest antimalarial activity alone, but have been shown to serve as "chemosensitizers", in that they effectively reverse chloroquine resistance in P. chabaudi in a murine model (43). Similar compounds such as 33 are more effective than verapamil, a well known multidrug resistance reverser, as chemosensitizers in the chloroquine resistant W2 clone of P. falciparum (44). 2,4-Diaminopyrimidine dihydrofolate reductase inhibitors related to pyrimethamine and trimethoprim show promising antimalarial activity against pyrimethamine-resistant strains of P. falciparum, typified by 34 (IC50 = 0.05 |iM) and 35 (IC50 = 0.5 |iM), respectively (45).

Screening of known bis-phosphonates such as 36 (IC5o = 5.1 nM) has shown that these compounds can exhibit good antimalarial activity, and also are effective against other parasitic organisms such as trypanosomes and leishmania (46). Finally, a novel series of phenylalanine-statin analogues have been described that are potent, specific inhibitors of the aspartyl protease plasmepsin II (e.g. compound 37, Ki = 0.54 nM)(47). Unfortunately, these compounds do not traverse cell membranes effectively, and thus have relatively low IC50 values against P. falciparum. Second generation inhibitors have now been developed that are still effective plasmepsin II inhibitors, but show greater efficacy in an infected erythrocyte in vitro assay (e.g. compound 38, Ki = 68 nM, ED50 = 1.6 nM) (48). Additional studies are required to optimize the structure of plasmepsin II inhibitors.

Conclusion - It is evident from the studies described above that there are many new and promising avenues for antimalarial research. Identification and exploitation of newly identified, parasite-specific targets has and will continue to enhance the ability to design effective small molecules for use as antimalarial agents. However, careful examination of the references appended to this report reveals that much of the effort to discover effective treatments for malaria is being expended in Europe, or in Third World countries in which the disease is endemic. In light of the impact of resistant strains of Plasmodium, additional funding will be required to fuel antimalarial research, and more of this work will need to be done in developed nations, including the United States. If these steps are taken, there is great hope that malaria can be essentially eliminated as a major cause of global morbidity.

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